Sodium Glucose Cotransporter Inhibitors for the Treatment of Diabetes

Abstract

Worldwide, the incidence of diabetes mellitus, a chronic metabolic disease that results in four million deaths from it and associated complications annually, is increasing and its treatment is an enormous public health concern. Type 1 diabetes is treated by insulin, but a variety of drugs are used to treat the more prevalent type 2 diabetes. Inhibitors of sodium glucose cotransporters (SGLTs) are the newest drugs to reach the market to achieve the blood‐glucose control needed to treat type 2 diabetes. SGLT1 and 2 carry out renal reabsorption of more than 90% of glucose from urine against a concentration gradient using the electrochemical energy from the cotransport of sodium ions. Blocking SGLTs causes excess glucose to be excreted through the urine, reducing blood sugar. The first known SGLT inhibitor was the O ‐glycosylated flavonoid natural product phlorizin, which enabled the discovery of SGLTs and served as the initial lead compound for medicinal chemistry. O ‐ and C ‐Glycosylated flavonoid and dihydrochalcone natural products also inhibit SGLTs. The drugs on the market today, dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, and others, are all aryl C ‐glycosides. They are selective for SGLT2 over SGLT1 to avoid adverse side effects associated with SGLT1 inhibition. Studies have suggested that SGLT inhibitors have a renal and cardiovascular protective effect that is advantageous, although their use increases the risk of urinary tract and genital infections and ketoacidosis. SGLT inhibitors are in trials as an adjuvant to insulin for the treatment of type 1 diabetes.